Abstract
Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer.
Highlights
IntroductionPulmonary fibrosis is characterized by an over abundant accumulation of extracellular matrix (ECM)
Pulmonary fibrosis is characterized by an over abundant accumulation of extracellular matrix (ECM)collagen deposition in the distal lung interstitial tissue in association with an injured overlying epithelium and activated myofibroblasts
The precise role of H2O2-induced alveolar epithelial cell (AEC) mitochondrial DNA (mtDNA) damage in mediating pulmonary fibrosis is unclear, a possible causal role for H2O2 in promoting lung fibrosis is supported by several lines of evidence that we recently reviewed in detail elsewhere [35], and briefly summarize ; some of the key points are: (1) catalase, a H2O2 scavenger, blocks H2O2-induced human Idiopathic pulmonary fibrosis (IPF) fibroblast activation [34]; and prevents asbestos-induced fibrosis in rats [43,44]; (2) glutathione (GSH), an antioxidant, is diminished in IPF lungs and epithelial lining fluid [34,45,46]; and (3) n-acetyl cysteine (NAC), a GSH precursor, attenuates bleomycin-induced fibrosis in rodents and increases lung GSH
Summary
Pulmonary fibrosis is characterized by an over abundant accumulation of extracellular matrix (ECM). The precise role of H2O2-induced AEC mtDNA damage in mediating pulmonary fibrosis is unclear, a possible causal role for H2O2 in promoting lung fibrosis is supported by several lines of evidence that we recently reviewed in detail elsewhere [35], and briefly summarize ; some of the key points are: (1) catalase, a H2O2 scavenger, blocks H2O2-induced human IPF fibroblast activation [34]; and prevents asbestos-induced fibrosis in rats [43,44]; (2) glutathione (GSH), an antioxidant, is diminished in IPF lungs and epithelial lining fluid [34,45,46]; and (3) n-acetyl cysteine (NAC), a GSH precursor, attenuates bleomycin-induced fibrosis in rodents and increases lung GSH levels, NAC administration to patients with IPF was recently proven no better than placebo [47,48]. 4 isoforms, in the pathogenesis of pulmonary fibrosis, including AEC apoptosis and apoptosis-resistant myofibroblasts [49,50,51,52,53]
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